In our recent effort to understand the basis for adaptation to high altitude hypoxia in human subjects, we analyzed the whole genome of Ethiopians residing at high altitude (>3,500m above sea level) for genetic variation. Humans on the Ethiopian mountains are well adapted to high altitude and do not suffer from Chronic Mountain Sickness such as those in the Andes. Using cross-population tests of selection, we identified genomic regions with significant loss of diversity in the Ethiopians, indicative of selective sweeps. Indeed, we discovered a number of such DNA regions on several chromosomes with specific genes embedded in them. In order to elucidate the potential role of these genes in hypoxia response and tolerance, we experimentally tested whether these genes were involved in hypoxia, in either Drosophila melanogaster or mice, thus providing additional evidence for their role in hypoxia in humans. One of these DNA selected regions on chromosome 13 harbored the gene Endothelin Receptor B (EDNRB). In mammals, this gene encodes for a receptor for an endothelin ligand, a potent vasoactive peptide that activates a signaling cascade that promotes blood vessel constriction. Since a) there is literature showing that inhibition of endothelin receptors is beneficial for adaptation to high altitude hypoxia, especially regarding pulmonary hypertension and b) EDNRB is present mostly in the cardiovascular system (CV), we focus this proposal on the study of EDNRB and the effects of its down-regulation on the CV system and on the cellular and molecular acute responses to hypoxia. Towards this goal, we have created an EDNRB knock-down in mice (EDNRB+/-) to study the role of this particular gene in the CV system in acute hypoxia. Our overall hypothesis is that EDNRB plays an important protective role in acute hypoxic stress. This hypothesis will be addressed in the experiments of the following Specific Aims: Specific Aim 1: Study the cardiovascular (CV) function in EDNRB+/- and demonstrate that EDNRB down-regulation or inhibition preserves CV function in acute hypoxia as compared to wild type mice. Specific Aim 2: Dissect the molecular mechanisms that are fundamental to the preservation of the CV function during acute hypoxia in EDNRB+/- mice.